Phase I/II Study of 9-ING-41, a Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined With Chemotherapy, in Patients With Refractory Hematologic Malignancies or Solid Tumors
Study Identifier:
1801
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
N/A
Study Complete
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Study Summary
To evaluate the safety and efficacy of 9-ING-41, a potent GSK-3ß inhibitor, as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.
The 1801 study will have three parts:
Part 1 (9-ING-41 as monotherapy): The standard 3+3 dose escalation design will be applied to all dose cohorts until the Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) is identified
Part 2: 9-ING-41 combined with standard anticancer agents: The 3+3 dose escalation study design will be used for 6 chemotherapy combination regimens (9-ING-41 plus gemcitabine, doxorubicin, lomustine, carboplatin, nab-paclitaxel plus gemcitabine, paclitaxel plus carboplatin) to identify the MTD/RP2D of each regimen. Part 2 will be started after a maximum of 3 dose escalations of 9-ING-41 as a single agent in Part 1. The starting dose level in Part 2 of 9-ING-41 within the six combination regimens will be the 3rd dose level of single agent 9-ING-41 (or lower if the IDMC so recommends). Dose escalations of 9-ING-41 as a single agent in Part 1 will continue in parallel with dose escalations of 9-ING-41 in combination treatments in Part 2.
Part 3: Assessment of activity of 9-ING-41 based combination regimens: The primary objective for Study Part 3 is to assess the clinical benefit of each of the six 9-ING-41-based combination regimens.
To evaluate the safety and efficacy of 9-ING-41 as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.
To evaluate safety and efficacy of 9-ING-41 as monotherapy and combination therapy in pts with refractory cancers.
Part 1 and 2:
Evaluate the safety, describe dose-limiting toxicities (DLTs), determine the maximum tolerated dose and the recommended phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Part 1) and as combination therapy (Part 2).
Part 3:
(Simon 2-Stage Phase 2) assess clinical benefit in pts treated with 9-ING-41-based combinations at the RP2D established in Part 2.
To evaluate the safety of 9-1NG-41 as monotherapy (Part 1) and in combination chemotherapies (Part 2) in patients with advanced malignancies using standard 3+3 escalation design
To determine the maximum tolerated dose (MTD) or the recommended Phase 2 study (RP2D)
Genomic sequencing reports were reviewed for somatic alterations deemed potentially actionable or biologically relevant. For those with PDAC, best response was determined using RECIST 1.1 for those who completed at least two cycles of treatment. Chi-square frequency statistics were used to show the observed versus expected rate of pathogenic variants between patients with disease control (complete response [CR], partial response [PR] or stable disease [SD]) and progressive disease (PD).
To evaluate the efficacy and safety of elraglusib in combination with GnP in advanced PDAC.
Pre-dose peripheral blood protein levels were examined as binary predictors of clinical outcome using optimal cutoff points determined by maximally selected rank statistics. In the aggregate Part 1 and 2 populations (n=45), we identified 13 CCSG that significantly stratified the cohort by overall survival (OS).
To compare the combination of elraglusib with gemcitabine/nab-paclitaxel (GnP) to GnP alone as a first line therapy in patients with metastatic pancreatic cancer (mPDAC).
To determine the 1-year survival rate of patients treated on the 9-ING-41 schedule chosen from the run-in stage of the study compared to the control arm.
Cytokine/chemokine correlative biomarker assays were performed.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
18+ years
Study Drug
Study Status
Indicates the current recruitment status or the expanded access status
Study Complete
Requirements information
Inclusion criteria
- Is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures.
- Is aged ≥ 18 years
- Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following:
- Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
- Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
- Malignancy has relapsed after standard therapy
- Malignancy for which there is no standard therapy that improves survival by at least 3 months
- Has evaluable tumor(s) by standard radiological and/or laboratory assessments as applicable to their malignancy - in Part 3, patients with solid tumors must have least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1 criteria, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI). In the case of patients with glioblastoma multiforme (GBM) or other central nervous system (CNS) tumors, the tumor must be measurable, defined as a clearly enhancing tumor with at two perpendicular diameters at entry equal or superior to 1cm.
- Has laboratory function within specified parameters (may be repeated):
- Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL
- Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase ≤ 3 (≤ 5 X the upper limit of normal (ULN) in the setting of liver metastasis or infiltration with malignant cells) x ULN; bilirubin ≤ 1.5 x ULN
- Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and Gault)
- Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3
- Serum amylase and lipase ≤ 1.5 x ULN
- Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
- Has received the final dose of any of the following treatments/ procedures with the specified minimum intervals before first dose of study drug (unless in the opinion of the investigator and the study medical coordinator the treatments/ procedures will not compromise patient safety or interfere with study conduct and with IDMC agreement):
- Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days or ≥ 5 half-lives (whichever is shorter)
- Focal radiation therapy - 7 days
- Systemic and topical corticosteroids - 7 days
- Surgery with general anesthesia - 7 days
- Surgery with local anesthesia - 3 days
- May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
- Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant during study participation and must agree to use effective contraceptive methods (hormonal or barrier method of birth control, or true abstinence) for the duration of study participation and in the following 90 days after discontinuation of study treatment
- Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 90 days after discontinuation of study treatment and use appropriate barrier contraception or true abstinence
- Must not be receiving any other investigational medicinal product
- Part 3 ARMB Inclusion Criteria: Patient -
- Is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures
- Is aged ≥ 18 years
- Has pathologically confirmed metastatic pancreatic cancer AND is previously untreated with systemic agents in the recurrence/metastatic setting.
- Must have at least 1 measurable lesion per RECIST v1.1, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI)
- Has laboratory function within specified parameters (may be repeated):
- e. Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 75,000/mL f. Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase ≤ 3 (≤ 10 X the upper limit of normal (ULN) in the setting of liver metastasis or infiltration with malignant cells) x ULN; bilirubin ≤ 1.5 x ULN Adequate renal function: creatinine clearance ≥ 30 mL/min (Cockcroft and Gault)
- Has Eastern Co-operative Oncology Group (ECOG) PS 0 or 1
- Has received the final dose of any of the following treatments/ procedures with the specified minimum intervals before first dose of study drug:
- Focal radiation therapy - 7 days
- Surgery with general anesthesia - 7 days
- Surgery with local anesthesia - 3 days
- May have received treatment with fluorouracil or gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment was received at least 6 months before study enrollment
- May have received neoadjuvant chemotherapy with FOLFIRINOX if last dose given at least 6 months before study enrollment
- May have received prior cytotoxic doses of systemic chemotherapy in the adjuvant setting if last dose given at least 6 months before study enrollment
- Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant during study participation and must agree to use effective contraceptive methods (hormonal or barrier method of birth control, or true abstinence) for the duration of study participation and in the following 90 days after discontinuation of study treatment
- Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 90 days after discontinuation of study treatment and use appropriate barrier contraception or true abstinence
- Must not be receiving any other investigational medicinal product
Exclusion criteria
- Is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures.
- Is aged ≥ 18 years
- Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following:
- Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
- Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
- Malignancy has relapsed after standard therapy
- Malignancy for which there is no standard therapy that improves survival by at least 3 months
- Has evaluable tumor(s) by standard radiological and/or laboratory assessments as applicable to their malignancy - in Part 3, patients with solid tumors must have least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1 criteria, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI). In the case of patients with glioblastoma multiforme (GBM) or other central nervous system (CNS) tumors, the tumor must be measurable, defined as a clearly enhancing tumor with at two perpendicular diameters at entry equal or superior to 1cm.
- Has laboratory function within specified parameters (may be repeated):
- Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL
- Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase ≤ 3 (≤ 5 X the upper limit of normal (ULN) in the setting of liver metastasis or infiltration with malignant cells) x ULN; bilirubin ≤ 1.5 x ULN
- Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and Gault)
- Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3
- Serum amylase and lipase ≤ 1.5 x ULN
- Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
- Has received the final dose of any of the following treatments/ procedures with the specified minimum intervals before first dose of study drug (unless in the opinion of the investigator and the study medical coordinator the treatments/ procedures will not compromise patient safety or interfere with study conduct and with IDMC agreement):
- Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days or ≥ 5 half-lives (whichever is shorter)
- Focal radiation therapy - 7 days
- Systemic and topical corticosteroids - 7 days
- Surgery with general anesthesia - 7 days
- Surgery with local anesthesia - 3 days
- May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
- Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant during study participation and must agree to use effective contraceptive methods (hormonal or barrier method of birth control, or true abstinence) for the duration of study participation and in the following 90 days after discontinuation of study treatment
- Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 90 days after discontinuation of study treatment and use appropriate barrier contraception or true abstinence
- Must not be receiving any other investigational medicinal product
- Is pregnant or lactating
- Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
- Has endocrine or acinar pancreatic carcinoma
- Has not recovered from clinically significant toxicities as a result of prior anticancer therapy, except alopecia and/or infertility. Recovery is defined as ≤ Grade 2 severity per CTCAE, v5.0
- Has significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, or stroke within 6 months of the first dose of study therapy, or uncontrolled cardiac arrhythmia
- Has had a myocardial infarction within 12 weeks of the first dose of study therapy or has electrocardiogram (ECG) abnormalities that are deemed medically relevant by the investigator
- Has symptomatic rapidly progressive brain metastases or leptomeningeal involvement as assessed by CT scan or MRI. Patients with stable brain metastases or leptomeningeal disease or slowly progressive disease are eligible provided that they have not required new treatments for this disease in a 28-day period before the first dose of study drug, and anticonvulsants and steroids are at a stable dose for a period of 14 days prior to the first dose of study drug
- Has had major surgery (not including placement of central lines) within 7 days prior to study entry or is planned to have major surgery during the course of the study (major surgery may be defined as any invasive operative procedure in which an extensive resection is performed, e.g., a body cavity is entered, organs are removed, or normal anatomy is altered. In general, if a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges), the surgery is considered major)
- Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation.
- Has received an investigational anti-cancer drug in the 14-day period before the first dose of study drug (or within 5 half-lives if longer) or is currently participating in another interventional clinical trial.
- Has a current active malignancy other than pancreatic cancer
- Is considered to be a member of a vulnerable population (for example, prisoners).
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Status
Recruitment on Hold
Condition(s) Treated at Site
Bladder
Breast Cancers
Bowel (Colorectal)
Non-Small Cell Lung Cancer
Ovarian
Pancreas
Prostate
Melanoma
Leukemia
Small Cell Lung
Renal
Unspecified Cancer
Glioblastoma
Gastric
Liver
Head & Neck
Hematological Cancer
Soft Tissue Sarcoma
Lymphoma, Non-Hodgkin's
Endometrial
Esophageal
Osteosarcoma
Cervical cancer
Neuroendocrine
Neuroblastoma
Fallopian Tube
Anal
Primary Peritoneal
Gallbladder
Bile Duct
Astrocytoma
Oligodendroglioma
Appendix Cancer